Thromboembolism involving the arterial or venous circulation or arising from the heart is a common cause of morbidity and mortality. Rapidly acting parenteral anticoagulants, such as heparin, are used for the prevention and initial treatment of thromboembolism and during revascularization procedures, whereas the slower-acting vitamin K antagonists (VKAs) are used for long-term therapy. The introduction of low-molecular-weight heparin (LMWH) and fondaparinux has simplified parenteral anticoagulant therapy, and these agents have replaced heparin for many indications. Development of new oral anticoagulants to replace VKAs has been slower than that of parenteral agents. Ximelagatran, an oral thrombin inhibitor, was briefly licensed in Europe but was withdrawn in 2006 because of potential hepatic toxicity. Although this set the field back for several years, the situation has changed with the recent introduction of dabigatran etexilate, a new oral thrombin inhibitor, and rivaroxaban, an oral factor Xa (fXa) inhibitor. Licensed in Europe and Canada for prevention of venous thromboembolism (VTE) in patients undergoing hip or knee arthroplasty, dabigatran etexilate and rivaroxaban streamline out-of-hospital thromboprophylaxis because the drugs can be given once daily in fixed doses without coagulation monitoring.
The greater unmet medical need, however, is to find a replacement for VKAs for long-term therapy, particularly stroke prevention in patients with atrial fibrillation (AF). The introduction of LMWH and fondaparinux simplified the initial management of arterial or venous thrombosis because these agents can be given subcutaneously without coagulation monitoring. Furthermore, the risk of heparin-induced thrombocytopenia is lower with LMWH than with heparin and nonexistent with fondaparinux. Nonetheless, the need for daily subcutaneous injection limits the long-term use of LMWH or fondaparinux. Other drawbacks include their potential for accumulation in patients with renal impairment, the lack of an antidote, and the risk of catheter thrombosis when these agents are used as the sole anticoagulant in patients undergoing percutaneous coronary intervention (PCI). With its long half-life, the lack of antidote is particularly problematic for fondaparinux.
Consequently, routine coagulation monitoring is necessary to ensure that the international normalized ratio (INR) is therapeutic because overanticoagulation is associated with an increased risk of hemorrhage, whereas underanticoagulation increases the risk of thrombosis. Such monitoring is inconvenient for patients and physicians and costly for the healthcare system. Furthermore, even with monitoring, the INR is frequently outside the therapeutic range. The many limitations of VKAs have resulted in their underuse for stroke prevention in eligible patients with AF, thereby creating a large unmet need that has prompted the development of new oral anticoagulants with potential advantages over existing agents.
Dabigatran etexilate, a prodrug of dabigatran, which reversibly inhibits the active site of thrombin, has a very limited oral bioavailability of ≈6%. Plasma levels of dabigatran peak ≈2 hours after drug administration.
Managing acute pathology of often relies on the addressing underlying pathology and symptoms of the disease. There is currently a need in the art for new compositions to treatment or delay of the onset of blood clotting disorders and its associated complications progression.